Chroman derivatives

ABSTRACT

Chroman derivatives of the formula I                    
     in which 
     R 1  is acyl having 1-6 C atoms, —CO—R 5  or an amino protective group, 
     R 2  is H or alkyl having 1-6 C atoms, 
     R 3 , R 4  in each case independently of one another are H, alkyl having 1-6 C atoms, CN, Hal or COOR 2 , 
     R 5  is phenyl which is unsubstituted or mono- or disubstituted by alkyl having 1-6 C atoms, OR 2  or Hal, 
     X is H, H or O, 
     Hal is F, Cl, Br or I, 
     and their salts, are suitable as intermediates in the synthesis of medicaments.

This application is a 371 of PCT/EP99/09333 filed Dec. 1, 1999.

The invention relates to chroman derivatives of the formula I

in which

R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protective group,

R² is H or alkyl having 1-6 C atoms,

R³, R⁴ in each case independently of one another are H, alkyl having 1-6C atoms, CN, Hal or COOR².

R⁵ is phenyl which is unsubstituted or mono- or disubstituted by alkylhaving 1-6 C atoms, OR² or Hal,

X is H,H or O,

Hal is F, Cl, Br or I,

and their salts.

The invention also relates to the optically active forms, the racemates,the enantiomers and also the hydrates and solvates, e.g. alcoholates, ofthese compounds.

Similar compounds are disclosed in EP 0 707 007.

The invention was based on the object of finding novel compounds whichcan be used, in particular, as intermediates in the synthesis ofmedicaments.

It has been found that the compounds of the formula I and their saltsare important intermediates for the preparation of medicaments, inparticular of those which show, for example, actions on the centralnervous system.

The invention relates to the chroman derivatives of the formula I andtheir salts.

Above and below, the radicals R¹, R², R³, R⁴, R⁵ and X have the meaningsindicated in the formulae I and II, if not expressly stated otherwise.

In the above formulae, alkyl has 1 to 6, preferably 1, 2, 3 or 4, Catoms. Alkyl is preferably methyl or ethyl, furthermore propyl,isopropyl, in addition also butyl, isobutyl, sec-butyl or tert-butyl.Acyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms Acyl is in particularacetyl, propionyl or butyryl.

R² is preferably H, in addition also methyl, ethyl or is propyl.

R³ and R¹ are preferably H.

R⁵ is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl.The radical R¹ is acyl, —CO—R⁵ or else an amino protective group whichis known per se; acetyl is particularly preferred.

The expression “amino protective group” is generally known and relatesto groups which are suitable for protecting (for blocking) an aminogroup from chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out at other positions in themolecule. Typical groups of this type are, in particular, unsubstitutedacyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protectivegroups are removed after the desired reaction (or reaction sequence),their nature and size is otherwise uncritical; however, those having1-20, in particular 1-8, C atoms are preferred. The expression “acylgroup” is to be interpreted in the widest sense in connection with thepresent process and the present compounds. It includes acyl groupsderived from, aliphatic, araliphacic, aromatic or heterocycliccarboxylic acids or sulfonic acids and also, in particular,alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.Examples of acyl groups of this type are alkanoyl such as acetyl,propionyl, butyryl: aralkanoyl such as phenylacetyl; aroyl such asbenzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonylsuch as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl,BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl suchas CBZ (carbobenzoxycarbonyl, also called 4-methoxybenzyloxycarbonyl,FMOC (9-fluorenylmethoxy-carbonyl); arylsulfonyl such as Mtr(4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protectivegroups are BOC and Mtr, an addition CBZ or FMOC.

The compounds of the formula I can have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula I includesall these forms.

The invention furthermore relates to a process for the preparation ofchroman derivatives of the formula I according to claim 1 and also oftheir salts, in which X is O, characterized in chat a compound of theformula II

in which R¹, R², R³, R⁴ have the meanings indicated in claim 1 and X isO, is hydrogenated with the aid of an enantiomerically enrichedcatalyst.

The invention also relates to a process for the preparation of chromanderivatives of the formula I according to claim 1 and also of theirsalts, in which X is H,H, characterized in that a compound of theformula II

in which R¹, R², R³, R⁴ have the meanings indicated in claim 1 and X isO, is hydrogenated with the aid of an enantiomerically enrichedcatalyst, and then reduced in the customary manner.

In particular, it has been found that (2-acetylaminomethyl)chromen-4-onecan be hydrogenated using various enantiomerically purerhodium-diphosphane complexes to give enantiomerically enriched(2-acetylaminomethyl)chroman-4-one.

The invention also relates to a process for the preparation of chromanderivatives of the formula I, characterized in that the enantiomericallyenriched catalyst is a transition metal complex.

Particularly preferably, the catalyst is a transition metal complexcomprising a metal selected from the group rhodium, iridium, rutheniumand palladium.

The invention furthermore relates to a process for the preparation ofchroman derivatives of the formula I, characterized in that the catalystis a transition metal complex in which the transition metal is complexedwith a chiral diphosphane ligand.

The ligands below may be mentioned by way of example:

Depending on the choice of the (R) or (S) enantiomer of the ligand inThe catalyst, the (R) or (S) enantiomer is obtained in an excess.

Precursors used for the chiral ligands are compounds such as, forexample, Rh(COD)₂OTf (rhodium-cyclooctadiene triflate), [Rh(COD)Cl]₂,Rh(COD)₂BF₄, [Ir(COD)Cl]₂, Ir(COD)₂BF₄ or [Ru(COD)Cl₂]_(x).

The compounds of the formula I and also the starting substances fortheir preparation are otherwise prepared by methods known per se, suchas are described in the literature (e.g. in the standard works such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), mainly under reactionconditions which are known and suitable for the reactions mentioned. Usecan also be made in this case of variants which are known per se, butnot mentioned here in greater detail.

If desired, the starting substances can also be formed in situ such thatthey are not isolated from the reaction mixture, but immediately reactedfurther to give the compounds of the formula I.

The compounds of the formula II are known in some cases; the unknowncompounds can easily be prepared analogously to the known compounds.

The conversion of a compound of the formula II in which X is O into acompound of the formula I in which X is O is carried out according tothe invention using hydrogen gas with the aid of an enantiomericallyenriched catalyst in an inert solvent such as, for example, methanol orethanol.

Suitable inert solvents are furthermore, for example, hydrocarbons suchas hexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, chloroform or dichloromethane; alcohols such asisopropanol, n-propanol, n-butanol or tert-butanol; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl or monoethyl ether(methyl glycol or ethyl glycol), ethylene glycol dimethyl ether(diglyme); ketones such as acetone or butanone; amides such asacetamide, dimethylacetamide or dimethylformamide (DMF); nitrites suchas acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbondisulfide; nitro compounds such as nitromethane or nitrobenzene; esterssuch as ethyl acetate, and optionally also mixtures of the solventsmentioned with one another or mixtures with water.

The reaction time of the enantioselective hydrogenation, depending onthe conditions used, is between a few minutes and 14 days; the reactiontemperature is between 0 and 150°, normally between 20 and 130°.

Customarily, the catalyst/substrate ratio is between 1:2000 and 1:50,particularly preferably 1:1000 and 1:100. The reaction time is then, forexample, between 3 and 20 hours. The hydrogenation is carried out under1-200 bar of hydrogen, preferably at 3-100 bar.

The conversion of a compound of the formula II in which X is O into acompound of the formula I in which X is H,H is carried out according t othe invention using hydrogen gas with the aid of an enantiomericallyenriched catalyst in an inert solvent such as methanol or ethanol, suchas described above, followed by a conversion of the 4-oxo group into amethylene group according to known conditions. The reduction ispreferably carried out using hydrogen gas under transition metalcatalysis (for example by hydrogenation on Raney nickel or Pd-carbon inan inert solvent such as methanol or ethanol).

The conversion of compounds of the formula I in which R³, R⁴ is COOalkylinto compound s of the formula I in which R³, R⁴ is COOH is carried out,for example, using NaOH or KOH in water, water-THF or water-dioxane attemperatures between 0 and 100°.

The removal of a radical R¹ from a compound of the formula I is carriedout—depending on the protective group used—for example using strongacids, expediently using TFA (trifoluoroacetic acid) or perchloric acid,but also using other strong inorganic acids such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids such as trichloroaceticacid or sulfonic acids such as benzene or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but not alwaysnecessary. Suitable inert solvents are preferably organic solvents, forexample carboxylic acids such as acetic acid, ethers such astetrahydrofuran or dioxane, amides such as dimethylformamide,halogenated hydrocarbons such as dichloromethane, in addition alsoalcohols such as methanol, ethanol or isopropanol and also water. Inaddition, mixtures of the abovementioned solvents are possible. TFA ispreferably used in an excess without addition of a further solvent,perchloric acid in the form of a mixture of acetic acid and 70%perchloric acid in the ratio 9:1. The reaction temperatures areexpediently between approximately 0 and approximately 50°; the reactionis preferably carried out between 15 and 30°.

The BOC group is preferably removed using TFA in dichloromethane orusing approximately 3 to 5 N hydrochloric acid in dioxane at 15-30°. Theremoval of the acetyl group is carried out according to customarymethods (P. J. Kocienski, Protecting Groups, Georg Thieme Verlag,Stuttgart, 1994).

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) canbe removed, for example, by treating with hydrogen in the presence of acatalyst (e.g. of a noble metal catalyst such as palladium, expedientlyon a support such as carbon). Suitable solvents in this case are thoseindicated above, in particular, for example, alcohols such as methanolor ethanol or amides such as DMF. As a rule, the hydrogenolysis iscarried out at temperatures between approximately 0 and 100° andpressures between approximately 1 and 200 bar, preferably at 20-30° and1-10 bar.

A base of the formula I can be converted into the associated acidaddition salt using an acid, for example by reaction of equivalentamounts of the base and of the acid in an inert solvent such as ethanoland subsequent evaporation. For this reaction, suitable acids areparticularly those which yield physiologically acceptable salts. Thusinorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalicacids such as hydrochloric acid or hydrobromic acid, phosphoric acidssuch as orthophosphoric acid, sulfamic acid, in addition organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,e.g. formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methaneor ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- anddisulfonic acids and laurylsulfuric acid. Salts with physiologicallyunacceptable acids, e.g. picrates, can be used for the isolation and/orpurification of the compounds of the formula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal or alkaline earthmetal salts, using bases (e.g. sodium or potassium hydroxide orcarbonate), or into the corresponding ammonium salts.

The invention furthermore relates to the use of the compounds of theformula I as intermediates for the synthesis of medicaments. Appropriatemedicaments are described, for example, in EP 0 707 007.

The invention accordingly relates in particular to the use of thecompounds of the formula I according to claim 1 in the synthesis of

(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman and itssalts, characterized in that

a) a compound of the formula II

 in which

R¹ has the meaning indicated in claim 1,

R², R³ and R⁴ are H and X is O,

is hydrogenated with the aid of an enantiomerically enriched catalyst,

b) in that, from the enantiomerically enriched mixture of the (R) and(S) compounds of the formula I thus obtained, in which

R¹ has the meaning indicated in claim 1,

R², R³ and R⁴ are H and X is O.

the enantiomerically pure (R) compound of the formula I, in which

R¹ has the meaning indicated in claim 1,

R², R³ and R⁴ are H and X is O,

is obtained by crystallization, in that

c) the enantiomerically pure (R) compound of the formula I, in which

R¹ has the meaning indicated in claim 1,

R², R³ and R⁴ are H and X is O,

is then reduced in the customary manner, in that

d) the radical R¹ in which

R¹ has the meaning indicated in claim 1,

R², R³ and R⁴ are H and X is H,H,

is removed from the (R) compound of the formula I thus obtained, in that

e) the (R)-(chroman-2-ylmethyl)amine thus obtained is converted into itsacid addition salt and this is reacted in a known manner to give(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman and, ifappropriate, converted into its acid addition salt, where the recoveryof the (R) enantiomer can also be carried out by crystallization fromthe enantiomerically enriched (R,S) mixture after stage c) or afterstage d).

The invention furthermore relates to the use of the compounds of theformula I as intermediates for the synthesis of medicaments which showactions on the central nervous system.

Above and below, all temperatures are indicated in °C. In the followingexamples, “customary working up” means: if necessary, water is added,the mixture is adjusted, if necessary, depending on the constitution ofthe final product, to a pH of between 2 and 10 and extracted with ethylacetate or dichloromethane, the organic phase is separated off, driedover sodium sulfate and evaporated, and the residue is purified bychromatography on silica gel and/or by crystallization. R_(f) values onsilica gel.

EXAMPLE

Experimental data (complex preparation, hydrogenation, analyticalmethods):

All reactions were carried out under inert conditions (i.e. anhydrousand oxygen-free reaction conditions).

1. Preparation of the Catalyst/Substrate Solution 1.1. Example

11.2 mg of Rh(COD)₂OTf (rhodium-cyclooctadiene triflate) were dissolvedin 5 ml of methanol and cooled to 0° C. A cooled solution of 1.1 eq ofbisphosphane (e.g. 12.6 mg of (R,R)-Skewphos) in 5 ml of methanol wasthen added. After stirring at room temperature for 10 min, the complexsolution was treated with the substrate solution consisting of 110 mg of(2-acetylaminomethyl)chromen-4-one in 10 ml of methanol.

1.2. Example

51.4 mg of [Rh(COD)Cl]₂ were dissolved in 4 ml of the solvent mixturetoluene/methanol 5:1 and treated with a solution consisting of 5 ml oftoluene, 1 ml of methanol and 1.1 eq of bisphosphane (e.g. 130.6 mg of(R)-BINAP). 1 ml of this catalyst complex solution was added to 510.8 mgof (2-acetylaminomethyl)chromen-4-one, dissolved in 15 ml of toluene and3 ml of methanol.

2. Enantioselective Hydrogenation

The catalyst/substrate solution to be hydrogenated was filled into anautoclave in a countercurrent of protective gas. The protective gasatmosphere was replaced by flushing several times with hydrogen (1-5 barH₂ atmosphere). The batches analogous to 1.1. reacted even at roomtemperature and 5 bar of hydrogen. The catalysts analogous to 1.2.afforded the best results at 50° C. and 80 bar of hydrogen. As a rule,the hydrogenation was terminated after 15 hours.

3. Sampling and Analytical Methods

A sample was taken in a countercurrent of protective gas. The complexwas separated off by column chromatography on silica gel (eluent: ethylacetate) before the determination of the enantiomeric excesses.

The enantiomeric excess of the hydrogenation product was determined onthe chiral HPLC phase:

Column: Daicel Chiralcel OJ (I.D. × length/mm: 4.6 × 250) Eluent:n-hexane: i-propanol = 9:1 Flow: 0.8 ml/min (18 bar, 28° C.) Detection:UV 250 nm Retention: R_(t) (R) = 27 min; R_(t) (S) = 29 min

The concentration of the crude hydrogenation solution led to theprecipitation of the product. An increase in the enantiomeric excess wasdetected by means of fractional crystallization.

4. Further Reduction

After complete conversion was detected, the reduction of the keto groupwas carried out by means of palladium-carbon as a one-pot process. Thecrude ketone solution resulting from the homogeneous hydrogenation wastreated with 10% by weight water-moist palladium-carbon (e.g. 100 mg ofwater-moist Pd/C to 1 g of (2-acetylaminomethyl)chromen-4-one) and 1 mlof glacial acetic acid. Hydrogenation was carried out at a hydrogenpressure of 7 bar and 50° C. for 14 h.

5. Work-up and Analytical Methods

The palladium-carbon was removed by filtration. The enantiomeric excessof the hydrogenation product was determined on a chiral HPLC phase:

Column: Daicel Chiralcel OJ (I.D. × length/mm: 4.6 × 250) Eluent:n-hexane: i-propanol = 9:1 Flow: 0.8 ml/min (18 bar, 28° C.) Detection:UV 250 nm Retention: R_(t) (R) = 25 min; R_(t) (S) = 27 min

During the reduction with palladium-carbon, the enantiomeric excessremained unchanged.

The concentration of the crude hydrogenation solution led to theprecipitation of the product. An increase in the enantiomeric excess wasdetected by means of fractional crystallization.

Enantioselectivities of the Homogeneous Hydrogenation

Elab Complex:metal anion No. ligand (addition) Solvent Pressure % ee 1.18 Rh—OTf-(R,R)-EtDuphos CH₂Cl₂ 1 55 S 2. 13 Rh—OTf-(R,R)-EtDuphos THF 144 S 3. 14 Rh—OTf-(R,R)-EtDuphos MeOH 1 64 S 4. 15 Rh—OTf-(R,R)-EtDuphosEE 1 33 S 5.  6 Rh—OTf-(R,R)-EtDuphos iPrOH 1 20 S 6. 23aRh—OTf-(R,R)-EtDuphos MeOH 1 34 S 7. 23b Rh—OTf-(R,R)-EtDuphos MeOH 1 36S 8. 23c Rh—OTf-(R,R)-EtDuphos MeOH 5 45 S 9. 23d Rh—OTf-(R,R)-EtDuphosMeOH 5 31 S 10. 12 Ru—Cl₂-(R)-BINAP iPrOH 5 50 S (AgOOCCF₃) 11. 19Rh—ClO₄-(S,S)-Chiraphos iPrOH 1 — 12. 20 Rh—OTf-(S,S)-DIOP THF 1 rac.13. 20 Rh—OTf-(S,S)-DIOP THF 3  8 R 14. 21 Rh—OTf(R,R)-Skewphos THF 1 —15. 22b Rh—OTf-(S,S)-BPPM MeOH 1  7 S 16. 24a Rh—OTf-(R,S)-BPPFOH MeOH 154 R 17. 24b Rh—OTf-(R,S)-BPPPOH MeOH 1 54 R 18. 24c Rh—OTf-(R,S)-BPPFOHMeOH 5 63 R 19. 25a Rh—OTf-(R)-BINAP MeOH 1  1 R 20. 25bRh—OTf-(R)-BINAP MeOH 5 rac. 21. 26a Rh—OTf-(S,S)-Norphos MeOH 1 42 R22. 26b Rh—OTf-(S,S)-Norphos MeOH 5 60 R 23. 26c Rh—OTf-(S,S)-NorphosiPrOH 5 12 R 24. 26d Rh—OTf-(S,S)-Norphos THF 5  3 R 25. 27aRh—OTf-(S,S)-Norphos MeOH 8 64 R 26. 27b Rh—Cl-(S,S)-Norphos MeOH 8 40 R27. 27c Rh—OTf-(S,S)-Norphos MeOH 30 65 R 28. 27d Rh—OTf-(S,S)-NorphosMeOH 60 64 R 29. 28a Rh—OTf-(R,R)-EtDUPhos MeOH 10 16 S 30. 28bRh—OTf-(R,R)-EtDUPhos MeOH 30 28 S 31. 29a Rh—OTf-(R,R)-BPPFOH MeOH 1055 R 32. 29b Rh—OTf-(R,S)-BPPFOH MeOH 30 56 R 33. 37Rh—ClO₄-(S,S)-Chiraphos MeOH 10 30 R 34. 38 Rh—OTf-(S,S)-DIOP MeOH 10rac. 35. 39 Rh—OTf-(R,R)-Skewphos MeOH 10 46 S 36. 40 Rh—OTf-(S,S)-BPPMMeOH 10  9 S 37. 41 Ir—Cl-(S,S)-DIOP MeOH 10  8 R 38. 42Ir—Cl-(S,S)-DIOP CH₂Cl₂ 10  7 S 0. 43 Ir—Cl-(S,S)-DIOP (+I) MeOH 10 — 1.44 Ir—Cl-(S,S)-DIOP (+I) MeOH 30 — 2. 45 Ir—Cl-(S,S)-DIOP (+I + MeOH 10— CH₃COOH) 3. 46 Ir—OTf-(S,S)-DIOP MeOH 10 11 R 4. 47 Ir—OTf-(S,S)-DIOP(+I) MeOH 10 39 R 5. 49 Rh—OTf-(S,S)-Norphos MeOH 10, RT 57 R 6. 50Rh—OTf-(S,S)-Norphos MeOH 10, 50° C. 60 R 7. 52 Rh—BF₄-(R,S)-PFctB MeOH10, 50° C. 33 S 8. 54 Rh—Cl-(R)-BINAP Tol:MeOH 5:1 80, 50° C. 91 S 9. 59Rh—Cl-(S,S)-Norphos Tol:MeOH 5:1 80, 50° C. 19 R 10. 62 crude 59/Pd/CTol:MeOH 5:1  7, 50° C. 18 R

What is claimed is:
 1. A chroman compound of formula I

in which R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protectivegroup, R² is H or alkyl having 1-6 C atoms, R³, R⁴ in each caseindependently of one another are H, alkyl having 1-6 C atoms, CN, Hal orCOOR², R⁵ is phenyl which is unsubstituted or mono- or disubstituted byalkyl having 1-6 C atoms, OR² or Hal, X is H, H or O, Hal is F, Cl, Bror I, or a physiologically acceptable salt thereof, wherein saidcompound is not N-(Chroman-2-ylmethyl)-cyclopropane carboxylic acidamide.
 2. An enantiomer of the compound of claim
 1. 3. The compoundaccording to claim 1, wherein said compound is a)N-(4-oxochroman-2-ylmethyl)acetamide; b)N-(chroman-2-ylmethyl)acetamide; c)(S)-N-(4-oxochroman-2-ylmethyl)acetamide; d)(R)-N-(4-oxochroman-2-ylmethyl)acetamide; e)(S)-N-(chroman-2-ylmethyl)acetamide; or f)(R)-N-(chroman-2-ylmethyl)acetamide.
 4. A process for the preparation ofa compound according to claim 1 in which X is O, wherein a compound offormula II

in which R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protectivegroup, R² is H or alkyl having 1-6 C atoms, R³, R⁴ in each caseindependently of one another are H, alkyl having 1-6 C atoms, CN, Hal orCOOR², and X is O, is hydrogenated with a chiral catalyst.
 5. A processfor the preparation of the compound according to claim 1 in which X isH, H, wherein a compound of formula II

in which R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protectivegroup, R² is H or alkyl having 1-6 C atoms, R³, R⁴ in each caseindependently of one another are H, alkyl having 1-6 C atoms, CN, Hal orCOOR², and X is O, is hydrogenated with a chiral catalyst, and reduced.6. The process according to claim 4, wherein the catalyst is atransition metal complex.
 7. The process according to claim 4, whereinthe catalyst is a transition metal complex comprising rhodium, iridium,ruthenium or palladium.
 8. The process according to claim 4, wherein thecatalyst is a transition metal complex in which the a transition metalis complexed with a chiral diphosphane ligand.
 9. A method for thesynthesis of(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman, or a saltthereof, comprising: a) hydrogenating with a chiral catalyst, a compoundof the formula II

 in which R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protectivegroup, R², R³ and R⁴ are H and X is O; b) crystalizing the enantiomeric(R) compound from the enantiomerically enriched mixture of (R) and (S)compounds thus obtained; c) reducing the enantiomeric (R) compound fromb); d) removing the R¹ radical from the (R) compound thus obtained toproduce (R)-(chroman-2-ylmethyl)amine; and e) converting the(R)-(chroman-2-ylmethyl)amine to its an acid addition salt and reactingsaid acid addition salt to give(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman.
 10. Themethod of claim 9, wherein(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman isconverted to an acid addition salt.
 11. A method for the synthesis of(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman, or a saltthereof, comprising: a) hydrogenating with a chiral catalyst, a compoundof the formula II

 in which R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protectivegroup, R², R³ and R⁴ are H and X is O; b) reducing the enantiomericallyenriched mixture of (R) and (S) compounds thus obtained; c) crystalizingthe enantiomeric (R) compound from the enantiomerically enriched mixtureof (R) and (S) compounds; d) removing the R¹ radical from the (R)compound thus obtained to produce (R)-(chroman-2-ylmethyl)amine; and e)converting the (R)-(chroman-2-ylmethyl)amine to an acid addition saltand reacting said acid addition salt to give(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman.
 12. Themethod of claim 11, wherein(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman isconverted to an acid addition salt.
 13. A method for the synthesis of(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman, or a saltthereof, comprising: a) hydrogenating with a chrial catalyst, a compoundof the formula II

 in which R¹ is acyl having 1-6 C atoms, —CO—R⁵ or an amino protectivegroup, R², R³ and R⁴ are H and X is O; b) reducing the enantiomericallyenriched mixture of (R) and (S) compounds thus obtained; c) removing theR¹ radical from the compounds thus obtained; d) crystalizing theenantiomeric (R) compound from the enantiomerically enriched mixture of(R) and (S) compounds; and e) converting the enantiomeric (R) compoundto an acid addition salt and reacting said acid addition salt to give(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman.
 14. Themethod of claim 13, wherein(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman isconverted to an acid addition salt.
 15. A pharmaceutical compositioncomprising a compound of claim
 1. 16. The compound of claim 1, whereinR¹ is acyl with 1-6 C atoms or —CO—R⁵.
 17. The process according toclaim 5, wherein the catalyst is a transition metal complex.
 18. Theprocess according to claim 5, wherein the catalyst is a transition metalcomplex comprising rhodium, iridium, ruthenium or palladium.
 19. Theprocess according to claim 5, wherein the catalyst is a transition metalcomplex in which the transition metal is complexed with a chiraldiphosphane ligand.
 20. The process according to claim 9, wherein thecatalyst is a transition metal complex.
 21. The process according toclaim 9, wherein the catalyst is a transition metal complex comprisingrhodium, iridium, ruthenium or palladium.
 22. The process according toclaim 9, wherein the catalyst is a transition metal complex in which thetransition metal is complexed with a chiral diphosphane ligand.
 23. Theprocess according to claim 11, wherein the catalyst is a transitionmetal complex.
 24. The process according to claim 11, wherein thecatalyst is a transition metal complex comprising rhodium, iridium,ruthenium or palladium.
 25. The process according to claim 11, whereinthe catalyst is a transition metal complex in which the transition metalis complexed with a chiral diphosphane ligand.
 26. The process accordingto claim 13, wherein the catalyst is a transition metal complex.
 27. Theprocess according to claim 13, wherein the catalyst is a transitionmetal complex comprising rhodium, iridium, ruthenium or palladium. 28.The process according to claim 13, wherein the catalyst is a transitionmetal complex in which the transition metal is complexed with a chiraldiphosphane ligand.